Sphingolipids and cancer: ceramide and sphingosine-1-phosphate in the regulation of cell death and drug resistance.
Sphingolipids and cancer: ceramide and sphingosine-1-phosphate in the regulation of cell death and drug resistance.
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DOI：
10.2217/fon.10.116
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发表时间：
2010-10
期刊：
影响因子：
--
通讯作者：
Ogretmen B
中科院分区：
文献类型：
--
作者：
Ponnusamy S;Meyers-Needham M;Senkal CE;Saddoughi SA;Sentelle D;Selvam SP;Salas A;Ogretmen B
鞘脂已成为生物效应分子，控制癌症细胞生长和增殖的各个方面，这正在成为世界上最致命的疾病。这些脂质分子也与癌症化疗药物的作用机制有关。神经酰胺是鞘脂代谢的中心分子，通常介导抗增殖反应，如细胞生长抑制、凋亡诱导、衰老调节、内质网应激反应和/或自噬。有趣的是，最近的研究表明，新产生的神经酰胺可能在促进/抑制肿瘤中具有不同的和相反的作用，并且这些活性是基于它们的脂肪酸链长度、亚细胞定位和/或直接下游靶点。例如，在头颈癌细胞中，神经酰胺合成酶6/C16-神经酰胺成瘾被揭示，这与肿瘤生长增加有关，而其合成的下调导致ER应激诱导的细胞凋亡。相比之下，神经酰胺合酶1产生的C18-神经酰胺已显示在各种癌症模型中原位和体内抑制肿瘤生长。此外，神经酰胺代谢产生鞘氨醇-1-磷酸（S1 P）的鞘氨醇激酶1和2介导，或不参与G-蛋白偶联的S1 P受体信号，促生存，血管生成，转移和/或耐药诱导的细胞凋亡。重要的是，最近的研究结果，鞘脂代谢和信号调节肿瘤生长和进展的机制，如确定直接的鞘脂细胞内蛋白质的目标，已经成为新的化疗策略的发展的关键。因此，在这篇文章中，我们将介绍最近的研究结论，这些研究描述了神经酰胺脱氢酶和/或S1 P在调节癌症发病机制中新生神经酰胺的相反作用，以及基于鞘脂的癌症治疗和耐药性的发展。
Sphingolipids have emerged as bioeffector molecules, controlling various aspects of cell growth and proliferation in cancer, which is becoming the deadliest disease in the world. These lipid molecules have also been implicated in the mechanism of action of cancer chemotherapeutics. Ceramide, the central molecule of sphingolipid metabolism, generally mediates antiproliferative responses, such as cell growth inhibition, apoptosis induction, senescence modulation, endoplasmic reticulum stress responses and/or autophagy. Interestingly, recent studies suggest de novo-generated ceramides may have distinct and opposing roles in the promotion/suppression of tumors, and that these activities are based on their fatty acid chain lengths, subcellular localization and/or direct downstream targets. For example, in head and neck cancer cells, ceramide synthase 6/C16-ceramide addiction was revealed, and this was associated with increased tumor growth, whereas downregulation of its synthesis resulted in ER stress-induced apoptosis. By contrast, ceramide synthase 1-generated C18-ceramide has been shown to suppress tumor growth in various cancer models, both in situ and in vivo. In addition, ceramide metabolism to generate sphingosine-1-phosphate (S1P) by sphingosine kinases 1 and 2 mediates, with or without the involvement of G-protein-coupled S1P receptor signaling, prosurvival, angiogenesis, metastasis and/or resistance to drug-induced apoptosis. Importantly, recent findings regarding the mechanisms by which sphingolipid metabolism and signaling regulate tumor growth and progression, such as identifying direct intracellular protein targets of sphingolipids, have been key for the development of new chemotherapeutic strategies. Thus, in this article, we will present conclusions of recent studies that describe opposing roles of de novo-generated ceramides by ceramide synthases and/or S1P in the regulation of cancer pathogenesis, as well as the development of sphingolipid-based cancer therapeutics and drug resistance.
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影响因子：
4.8
作者：
Chalfant, CE;Kishikawa, K;Hannun, YA
通讯作者：
Hannun, YA
影响因子：
4.8
作者：
Chalfant, CE;Ogretmen, B;Hannun, YA
通讯作者：
Hannun, YA
DOI：
10.1126/science.1158111
发表时间：
2008-10-03
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Deng X;Yin X;Allan R;Lu DD;Maurer CW;Haimovitz-Friedman A;Fuks Z;Shaham S;Kolesnick R
通讯作者：
Kolesnick R
影响因子：
4.8
作者：
Bourbon, NA;Yun, J;Kester, M
通讯作者：
Kester, M
DOI：
10.1016/j.bbrc.2006.02.070
发表时间：
2006-04-21
影响因子：
3.1
作者：
Akao, Y;Banno, Y;Nozawa, Y
通讯作者：
Nozawa, Y